Some individuals smoke with the perception that smoking helps control body weight. Smokers gain an average of as much as 10 pounds in the months following smoking abstinence, with heavier and more-dependent smokers gaining more weight. Mean weight gain may be as much as 13 pounds at 1 year and 21 pounds over 5 years. Actual weight gain following smoking abstinence has been commonly associated with smoking relapse. The use of a pharmacologic agent to address weight concerns and weight gain while the smoker focuses on the behavioral aspects of stopping smoking offers an attractive clinical option. This K23 proposal requests a 5-year period of support for Dr. Ryan T. Hurt to complete a focused program of addiction training and research involving the use of lorcaserin (an FDA-approved weight loss medication) to prevent postcessation weight gain in overweight or obese smokers. Dr. Jon Ebbert, the applicant's mentor and expert in the area of pharmacological treatment of smoking, will oversee completion of the applicant's career development goals. Dr. Doo-Sup Choi, the applicant's co-mentor, is the Director of the Samuel C. Johnson Genomics of Addiction Program and is an expert in addiction. The Mayo Clinic Nicotine Research Program will provide a strong infrastructure and support to complete both the training and research plans of the K23 award. In the proposed research plan we will randomize 100 nondiabetic, overweight or obese adult smokers to active lorcaserin or placebo for 24 weeks; all of the subjects will receive open-label varenicline for 12 weeks. The primary aim of this study is to assess the efficacy of a 24-week course of lorcaserin for decreasing weight gain after stopping smoking. Secondary aims will assess the efficacy of a 24-week course of lorcaserin for attenuating increases in waist circumference and BMI after stopping smoking. We will assess the efficacy of the combination of 24 weeks of lorcaserin and 12 weeks of varenicline on smoking abstinence rates. In addition, we will complete an exploratory arm in which we will treat 25 nondiabetic, overweight or obese adult smokers with lorcaserin monotherapy. We will assess the efficacy of lorcaserin on smoking abstinence rates.